[Novel Anticancer Strategy Targeting Switch Mechanisms in Two Types of Cell Death: Necrosis and Apoptosis]
1Faculty of Pharmaceutical Sciences, Tokyo University of Science.
Abstract:
Two types of cell death, necrosis and apoptosis, are defined in terms of cell death morphological features. We have been studying the mechanisms by which cell death processes are switched during the treatment of mouse tumor FM3A with anticancer, 5-fluoro-2'-deoxyuridine (FUdR): it induces original clone F28-7 to necrosis, but its sub-clone F28-7-A to apoptosis. We identified several such switch regulators of cell death: heat shock protein 90 (HSP90), lamin-B1, cytokeratin-19, and activating transcription factor 3 (ATF3), by using transcriptomic, proteomic analyses and siRNA screening. For example, the inhibition of HSP90 by its inhibitor geldanamycin in F28-7 caused a shift from necrosis to apoptosis. We also observed that the knockdown of lamin-B1, cytokeratin-19, or ATF3 expression in F28-7 resulted in a shift from necrosis to apoptosis. Recently, we used microRNA (miRNA, miR) microarray analyses to investigate the miRNA expression profiles in these sister cells. The miR-351 and miR-743a were expressed at higher levels in F28-7-A than in F28-7. Higher expression of miR-351 or miR-743a in F28-7, induced by transfecting the miR mimics, resulted in a switch of cell death mode: necrosis to apoptosis. Furthermore, transfection of an miR-351 inhibitor into F28-7-A resulted in morphological changes, and mode of cell death from apoptosis to necrosis. These findings suggest that the identified cell death regulators may have key roles in switching cell death mode. Possible mechanisms involving cell death regulators in the switch of necrosis or apoptosis are discussed. We propose a novel anticancer strategy targeting the switch regulators of necrosis or apoptosis.
Insights
Researchers identified key regulators, including heat shock protein 90 and specific microRNAs, that switch cancer cell death between necrosis and apoptosis. This discovery offers a novel anticancer strategy targeting these cell death switch mechanisms.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Cell death occurs via distinct modes: necrosis and apoptosis, differing in morphological features.
- The anticancer drug 5-fluoro-2'-deoxyuridine (FUdR) induces differential cell death responses in mouse tumor FM3A clones.
Purpose of the Study:
- To elucidate the molecular mechanisms governing the switch between necrosis and apoptosis in cancer cells.
- To identify key regulators involved in modulating cell death pathways.
- To explore a novel anticancer strategy targeting these regulators.
Main Methods:
- Comparative analysis of original (F28-7) and sub-clone (F28-7-A) mouse tumor cells.
- Transcriptomic, proteomic, and siRNA screening to identify protein regulators (HSP90, lamin-B1, cytokeratin-19, ATF3).
- MicroRNA (miRNA) microarray analysis to profile miRNA expression.
- Functional studies using miRNA mimics and inhibitors to assess impact on cell death modes.
Main Results:
- Several proteins, including heat shock protein 90 (HSP90), lamin-B1, cytokeratin-19, and activating transcription factor 3 (ATF3), were identified as regulators.
- Inhibition of HSP90 or knockdown of lamin-B1, cytokeratin-19, or ATF3 shifted cell death from necrosis to apoptosis in F28-7 cells.
- MicroRNAs miR-351 and miR-743a were upregulated in the apoptosis-prone F28-7-A cells.
- Overexpression of miR-351 or miR-743a induced a switch from necrosis to apoptosis in F28-7 cells.
- Inhibition of miR-351 in F28-7-A cells induced a switch from apoptosis to necrosis.
Conclusions:
- Identified protein and miRNA regulators play critical roles in switching cell death modes between necrosis and apoptosis.
- These regulators offer potential targets for novel anticancer therapies aimed at manipulating cell death pathways.
- Understanding these switching mechanisms is crucial for developing effective cancer treatment strategies.
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